Early Stage Ovarian Cancer Patients Research Articles

Outcomes after fertility-sparing surgery of early-stage ovarian cancer: A nationwide population-based study.

Fertility-sparing surgery (FSS) is an alternative choice of young patients who have not completed their family planning and still have fertility needs. The aims of this study were to compare the outcomes of early-stage epithelial ovarian cancer (EOC) patients undergoing FSS and radical comprehensive staging surgery (RCS), and the suitability of FSS. A total of 1297 patients aged between 20 and 44 years with newly diagnosed early-stage EOC were recruited from the Taiwan Cancer Registry database between 2009 and 2017. Site-specific surgery codes were used to distinguish patients in FSS group or RCS group. Cancer-specific survival (CSS) was evaluated using Kaplan-Meier method with log-rank test and Cox regression model. There were 401 and 896 patients in FSS and RCS group. Patients in FSS group were with younger age and mostly had Stage I disease. In contrast, patients in RCS group were older. There were more Stage II, high-grade (Grade 3) disease, and adjuvant chemotherapy in RCS group. Stage and tumor grade were two independent factors correlating with CSS and the type of surgery showed no effect on CSS (HR: 1.09, 95% CI: 0.66-1.77, p = 0.73) in multivariable analysis. In multivariable analysis, the clear cell carcinoma group who underwent FSS demonstrated better CSS compared to those in the RCS group (HR: 0.28, 95% CI: 0.06-0.82, p = 0.04). A total of 17 women who underwent FSS developed second malignancies of the uterine corpus or contralateral ovary. FSS can be a safe alternative procedure in selected young patients of Stage I EOC who have fertility desire. Endometrial biopsy before or during FSS and regular surveillance to detect recurrence are mandatory for ovarian cancer patients undergoing FSS.

Preoperative and pre-chemotherapy CA-125 levels in high-risk early-stage ovarian cancer – An NRG/GOG study

ObjectivesTo determine clinical significance of preoperative and pre-chemotherapy CA-125 in high-risk early-stage epithelial ovarian cancer patients. MethodsAll patients with stage IA/IB and grade 3, stage IC, clear cell, or completed resected stage II cancer were enrolled in a phase III trial and treated with chemotherapy. Kaplan-Meier method and Cox proportional hazards model were used for statistical analyses. Results427 patients with high-risk early-stage ovarian cancer were enrolled. Of 213 patients with preoperative CA-125 data, 79% had elevated CA-125. Median preoperative CA-125 level was 103 U/mL. Patients with ≤10, 11–15, and > 15 cm tumors had median preoperative CA-125 levels of 62, 131 and 158 U/mL, respectively (p = 0.002). For the 350 patients with data for pre-chemotherapy CA-125 level, 69% had elevated pre-chemotherapy CA-125 above 35 U/mL with median value of 65 U/mL. However, age, race, stage, cell type and grade of disease were not correlated with CA-125 levels before and after surgery. On multivariate analysis, elevated pre-chemotherapy CA-125 independently predicted worse recurrence-free survival (HR = 2.13, 95% CI: 1.23–3.69; p = 0.007) and overall survival (HR = 1.99, 95% CI: 1.10–3.59; p = 0.022) after adjusting for age, stage, cell type and grade of disease. Compared to those with normal CA-125, patients with elevated pre-chemotherapy CA-125 had lower recurrence-free survival (RFS, 87% vs. 75%; p = 0.007) and overall survival (OS, 88% vs. 82%; p = 0.02). However, preoperative CA-125 was not prognostic of RFS (p = 0.699) or OS (p = 0.701). ConclusionsPreoperative CA-125 was elevated in nearly 80% of high-risk early-stage ovarian cancer patients. Pre-chemotherapy CA-125 was associated with recurrence-free and overall survival; however, preoperative CA-125 was not prognostic.

Abstract 5556: Lemur tyrosine kinase 3 serves as a predictor of patient outcome and a target for the treatment of ovarian cancer

Abstract The objective of these in vitro and in vivo studies was to validate Lemur Tyrosine Kinase 3 (LMTK3) as a specific target and predictor of clinical outcome in ovarian cancer. LMTK3 belongs to a family of regulated tyrosine kinases with three structurally related isoforms, LMTK1, LMTK2, and LMTK3. Both nuclear and cytoplasmic LMTK3 expressions correlated with tumor grade and patient survival in cancers such as breast and colorectal cancer. We tested the clinical significance of the LMTK3 gene by immunohistochemistry (IHC) using LMTK3 monoclonal antibody on formalin-fixed paraffin-embedded sections (FFPE) collected from 204 early-stage (stage I-II) ovarian cancer patients. Results from this IHC LMTK3 study revealed a higher cytoplasmic to nuclear localization of LMTK3 correlated with worse overall survival (P<0.01). Further investigation of LMTK3’s prognostic value by screening LMTK3 signaling in 270 stage III-IV ovarian cancer patients is ongoing. We utilized the MTT ((3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay for testing the killing efficacy of targeting LMTK3 by a monoclonal antibody, siRNA, and specific LMTK3 binding peptides (LMTK3BP) in ovarian cancer cell lines SKOV3, MDAH-2774, A2780, and TOV-21G. Treatment with LMTK3 specific monoclonal antibody, siRNA, and LMTK3BP significantly induced killing of both chemosensitive and chemoresistant ovarian cancer cells without affecting normal cells in vitro. Moreover, we observed this killing as synergistic with both Cisplatin and Taxotere treatment in vitro. Lastly, we used an A2780 cell line derived orthotopic xenograft mouse model of ovarian cancer to test the efficacy of specific LMTK3BP in vivo. Strikingly, LMTK3BP 20 mg/kg IV dose given three times a week for three weeks showed a 35% tumor reduction. Furthermore, in vivo safety studies showed no signs of toxicity of the LMTK3BP, even at a very high dose of 40 mg/kg. Thus, with dose optimization in ongoing experiments, we could expect a higher efficacy. In conclusion, this study highlighted the importance of LMTK3 as a predictor of patient clinical outcome and potential target for treatment in ovarian cancer. Citation Format: Thea K. Kirsch-Mangu, Axel S. Tullberg, Anna Portela, Khalil Helou, Ghassan M. Saed. Lemur tyrosine kinase 3 serves as a predictor of patient outcome and a target for the treatment of ovarian cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5556.

Oncologic and obstetric outcomes of early-stage epithelial ovarian cancer patients who underwent fertility-sparing surgery: A retrospective study.

This study aimed to assess the long-term oncologic and obstetric outcomes of women with epithelial ovarian cancer who underwent fertility-sparing surgery. A total of 68 patients observed between March 2007 and July 2021 were included in this retrospective study. Unilateral salpingo-oophorectomy and uterine preservation with staging surgery were the main procedures for fertility-sparing surgery. Disease-free, overall survival, and obstetric outcomes were measured as primary outcomes. The median age of the patients was 30.5 years. The median follow-up time was 60.5months. Disease recurrence occurred in 15 (22.1%) of the patients. Five-year disease-free survival and overall survival (OS) percentages were 75.6% and 83.3%, respectively, for all stages. The FIGO (International Federation of Gynecology & Obstetrics) stage was the only significant factor that affected OS (P= 0.001). Twenty-three patients tried to conceive, and 15 (65.2%) patients became pregnant. Twelve (80%) pregnancies reached term and resulted in 15 live births. Chemotherapy administration and surgical intervention (cystectomy or unilateral salpingo-oophorectomy) showed no difference in pregnancy results (P= 0.806 and P= 0.066, respectively). Fertility preservation is safe for invasive epithelial ovarian cancer at early stages for women in the reproductive era. Disease recurrence and OS results are similar to standard treatment at early stages with decent obstetric outcomes.

The clinical and prognostic significance of pre-chemotherapy serum CA-125 in high-risk early stage ovarian cancer: An NRG/GOG ancillary study

ObjectivesTo determine the clinical and prognostic significance of CA-125 trends prior to, during, and after chemotherapy in high-risk early-stage epithelial ovarian cancer patients. MethodsAll patients were enrolled in a phase III randomized trial (GOG 157) following upfront surgery for grade 3 stage IA/IB, stage IC, or stage II disease, and had been treated with either three or six cycles of carboplatin/paclitaxel. Kaplan-Meier method and Cox proportional hazards model were used to evaluate recurrence-free survival (RFS) and overall survival (OS). ResultsOf 350 patients, the median pre-chemotherapy CA-125 was 65 (IQR: 31–129). 71% of Whites had an elevated CA-125 compared to 47% of non-Whites (p = 0.006). Following the first cycle of chemotherapy, 74% of those with elevated CA-125 had normalization. Those who had normalization of CA-125 after 1 cycle had significantly better 5-year RFS (81% vs. 65%, p = 0.003) and OS (87% vs. 75%, p = 0.009) compared to those who did not normalize (defined as ≤35 U/mL). The pattern of CA-125 change following chemotherapy cycle 1, from normal to normal vs. elevated to normal vs. elevated to elevated had corresponding RFS of 87% vs. 80% vs. 68% (p = 0.013), and OS of 92% vs. 88% vs. 77% (p = 0.009). However, the percent decline (p = 0.993) and absolute nadir normal value of CA-125 (0–10 vs. 11–35 U/mL) were not predictive of outcome (p = 0.4). ConclusionsNormal baseline CA125 and normalization of this biomarker after the first cycle of chemotherapy were associated with better survival in high-risk early-stage epithelial ovarian cancer patients.

Clinical calculator redefines prognosis for high-risk early-stage ovarian cancers and potential to guide treatment in the adjuvant setting

ObjectiveTo determine the utility of a clinical calculator to redefine prognosis and need for chemotherapy among patients with early-stage high-risk epithelial ovarian cancer. MethodsData were abstracted for stage I-II, high-risk ovarian cancer from the National Cancer Database from years 2005 to 2015. Based on demographic, pathologic, surgical, and laboratory characteristics, a clinical score was developed using Cox regression. Propensity score weighting was used to adjust for differences between patients who did and did not receive chemotherapy. ResultsOf 8188 patients with early-stage high-risk ovarian cancer, 6915 (84%) did and 1273 (16%) did not receive chemotherapy. A clinical calculator was created utilizing age, stage, histology, grade, tumor size, number of pelvic and paraaortic lymph nodes examined, the presence of malignant ascites, and CA125. The calculator divided patients into low, moderate, and high-risk groups with 5-year OS (overall survival) of 92%, 82%, and 66%, and 10-year OS of 85%, 67%, and 44%, respectively. Chemotherapy improved 5-year OS and 10-year OS in the high-risk group (56% to 73%; p < 0.001, 34% to 48%; p < 0.001). The moderate risk group had improved 5-year OS (80% to 85%; p = 0.01) but not 10-year OS (66% to 66%; p = 0.13). Chemotherapy did not improve 5-year or 10-year OS in low-risk patients (93% to 92%, p = 1.0, 86% to 84%, p = 0.99). ConclusionsThe prognosis among high-risk early-stage ovarian cancer patients is heterogeneous. This calculator may aid in patient-centered counseling regarding potential treatment benefits.

Adjuvant chemotherapy is not associated with improved overall survival with stage I endometrioid ovarian cancer patients in a SEER cohort

The objectives of this study was to investigate the prognostic significance of adjuvant chemotherapy in early-stage endometrioid ovarian cancer (EnOC) patients, especially those with grade II stage IA and IB and grade I stage IC, that are not explicitly recommended in the current National Comprehensive Cancer Network (NCCN) guidelines. This was a retrospective cohort study based on the Surveillance, Epidemiology and End Results (SEER) database, comprising 875 cases diagnosed with stage I EnOC from 2010 to 2018, of whom 441 (50%) and 434 (50%) received and did not receive chemotherapy, respectively. The Kaplan-Meier method was used for survival analysis, and the Cox multivariate regression analysis was performed to identify independent prognostic factors. Stratified survival analysis for adjuvant chemotherapy based on the recommendations of the NCCN Guidelines in stage I EnOC patients with different substages and grades showed that in this cohort adjuvant chemotherapy did not improve the survival of any of the stage I stratified substages group (p = 0.076, HR: 0.600, 95% CI: 0.342–1.054). Age ≥60 (p = 0.000, HR: 3.609, 95% CI: 2.156–6.039) and elevated CA125 (p = 0.028, HR: 2.480, 95% CI: 1.103–5.577) were independent risk factors associated with worse survival in stage I EnOC patients. In conclusion, chemotherapy would be unnecessary for stage I EnOC patients to improve the overall survival no matter substage and grade in our cohort.

Multi-analytical test based on serum miRNAs and proteins quantification for ovarian cancer early detection.

Advanced ovarian cancer is one of the most lethal gynecological tumor, mainly due to late diagnoses and acquired drug resistance. MicroRNAs (miRNAs) are small-non coding RNA acting as tumor suppressor/oncogenes differentially expressed in normal and epithelial ovarian cancer and has been recognized as a new class of tumor early detection biomarkers as they are released in blood fluids since tumor initiation process. Here, we evaluated by droplet digital PCR (ddPCR) circulating miRNAs in serum samples from healthy (N = 105) and untreated ovarian cancer patients (stages I to IV) (N = 72), grouped into a discovery/training and clinical validation set with the goal to identify the best classifier allowing the discrimination between earlier ovarian tumors from health controls women. The selection of 45 candidate miRNAs to be evaluated in the discovery set was based on miRNAs represented in ovarian cancer explorative commercial panels. We found six miRNAs showing increased levels in the blood of early or late-stage ovarian cancer groups compared to healthy controls. The serum levels of miR-320b and miR-141-3p were considered independent markers of malignancy in a multivariate logistic regression analysis. These markers were used to train diagnostic classifiers comprising miRNAs (miR-320b and miR-141-3p) and miRNAs combined with well-established ovarian cancer protein markers (miR-320b, miR-141-3p, CA-125 and HE4). The miRNA-based classifier was able to accurately discriminate early-stage ovarian cancer patients from health-controls in an independent sample set (Sensitivity = 80.0%, Specificity = 70.3%, AUC = 0.789). In addition, the integration of the serum proteins in the model markedly improved the performance (Sensitivity = 88.9%, Specificity = 100%, AUC = 1.000). A cross-study validation was carried out using four data series obtained from Gene Expression Omnibus (GEO), corroborating the performance of the miRNA-based classifier (AUCs ranging from 0.637 to 0.979). The clinical utility of the miRNA model should be validated in a prospective cohort in order to investigate their feasibility as an ovarian cancer early detection tool.

Primary Laparoscopic Surgery Does Not Affect the Prognosis of Early-Stage Ovarian Clear Cell Cancer.

PurposeMinimally invasive surgery (MIS) is performed frequently in early-stage ovarian cancer patients, especially in ovarian clear cell carcinoma (OCCC). The aim of this study was to investigate whether primary laparoscopic surgery influences prognosis in patients with early-stage OCCC.Patients and MethodsPatients with International Federation of Gynecology and Obstetrics (FIGO) stage I OCCC were retrospectively reviewed in two hospitals between April 2010 and August 2020. Clinical data were abstracted, and patients were followed up until February 2021. Patients were divided into open surgery (laparotomy) and laparoscopy groups, and the Kaplan–Meier method was applied to compare progression-free survival (PFS) and overall survival (OS) between the groups. Statistical differences were determined by the Log rank test.ResultsEighty-nine patients were included in the study; 20 (22.5%) and 69 (77.5%) patients underwent laparoscopic and open surgery, respectively. The patients’ characteristics were well-balanced except that patients in the laparoscopy group tended to have smaller tumors and lower frequency of omentectomy and lymphadenectomy compared with the open surgery group. The median follow-up duration was 42.6 and 36.5 months in the laparoscopy and open surgery groups, respectively. Nine (10.1%) patients developed recurrence, and 4 (4.5%) died of the disease; all in the open surgery group. The estimated 2-year PFS rates were 100.0% and 90.1%, and the estimated 5-year OS rates were 100.0% and 91.9% in the laparoscopy and open surgery groups, respectively. No significant survival differences were found between the groups.ConclusionSurvival was not compromised when primary laparoscopic surgery was performed in early-stage OCCC patients. A well-designed randomized controlled trial is warranted.

Management of gynecological cancers in the COVID-19 era: a survey from Turkey

Objective:This study aimed to investigate how gynecologic oncologists modified their patient management during Coronavirus disease-2019 (COVID-19) in Turkey.Material and Methods:An online survey was sent to gynecologic oncology specialists and fellows in Turkey. It included management questions about strategies for newly diagnosed or recurrent endometrial, cervical, ovarian and vulvar cancer during the pandemic. Participants were asked if treatment of these cancers can be delayed or not and, if yes, the duration of delay.Results:32.9% of surgeons prescribed oral or intrauterine progesterone for early stage, low-grade endometrial cancer. Conversely, 65.7% and 45.7% of the most surgeons did not change their management for early stage high-grade and advanced stage endometrial cancers respectively, as they perform surgery. 58% and 67.1% of the surgeons continued to prefer standard surgical treatment for microinvasive and early stage cervical cancers, respectively. Radiotherapy was preferred administered with hypofractionated doses for locally advanced cervical cancer (57.1%). While 67.1% of surgeons operated early stage ovarian cancer patients, 50% administered neoadjuvant chemotherapy (NACT) to all advanced stage ovarian cancers and 50% administered more cycles of NACT in preference to interval debulking surgery. 93.7% of the surgeons responded that treatment should not be delayed beyond eight weeks.Conclusion:Most Turkish gynecologic oncologists modified their management of gynecologic cancers due to the COVID-19 pandemic. While chemotherapy was preferred for ovarian cancer, postponement of the surgery, with or without non-surgical options, was considered for early stage, low-grade endometrial cancer. Treatment of gynecologic cancers should be decided on a case by case basis, taking into account local COVID-19 infection rates and availability of health facilities. Prognosis is also an important consideration if delay is contemplated. Standard treatment and normal time-frames should be used if possible. If not, a postponement for a maximum of eight weeks or referral to another center were acceptable alternatives.

The Prognostic Relevance of the Proliferation Markers Ki-67 and Plk1 in Early-Stage Ovarian Cancer Patients With Serous, Low-Grade Carcinoma Based on mRNA and Protein Expression.

Since type and duration of an appropriate adjuvant chemotherapy in early-stage ovarian cancer (OC) are still being debated, novel markers for a better stratification of these patients are of utmost importance for the design of an improved chemotherapeutical strategy. In contrast to numerous cancer studies on cellular proliferation based on the immunohistochemistry-driven evaluation of protein expression, we compared mRNA and protein expression of two independent markers of cellular proliferation, Ki-67 and Plk1, in a large cohort of 243 early-stage OC and their relationship with clinicopathological features and survival. Based on marker expression we demonstrate that early-stage OC patients (stages I/II, low-grade, serous) with high expression (Ki-67, Plk1) had a significantly shorter progression-free survival (PFS) and overall survival (OS) compared to patients with low expression (Ki-67, Plk1). Remarkably, based on mRNA expression this significant difference got lost in advanced stages (III/IV): At least for PFS, high levels of Ki-67 and Plk1 correlate with moderately better survival compared to patients with low expressing tumors. Our data suggest that in addition to Ki-67, Plk1 is a novel marker for the stratification of early-stage OC patients to maximize therapeutic efforts. Both, Ki-67 and Plk1, seem to be better suited in early-stages (I/II) as therapeutical targets compared to advanced-stages (III/IV) OC.

STUDY OF OVARIAN MALIGNANCY IN GYNEONCOLOGY UNIT IN ELSHATBY HOSPITAL IN ALEXANDRIA AS A TERTIARY REFFERAL CENTER

Malignant ovarian neoplasms cause more deaths than any other cancer of the female genital tract and is the seventh most common cancer diagnosed.Staging for ovarian cancer is principally surgical and should include total abdominal hysterectomy with bilateral salpingo-oophorectomy, only unilateral adnexectomy in fertility preservation surgery, at least infra-colic omentectomy, multiple peritoneal biopsies, lymph node sampling including pelvic and para-aortic lymph nodes up to renal veins, peritoneal wash and appendectomy in case of suspicion of mucinous histology.During initial surgery, early stage ovarian cancer patients are often incompletely staged. This oversight can have unfavorable sequelae for the prognosis of such patients, as the completeness of surgical staging is an independent prognostic parameter for survival. The aim of this work was to retrospectively review patients with ovarian malignancy from period 2017-2019 in gyne-oncology department of Elshatby hospital.This retrospective study was conducted on records of women admitted to gyne-oncology department in Elshatby hospital during period from 1/6/2017 to 1/6/2019 diagnosed with ovarian malignancy.

Serum Concentrations of Carotenoids and Fat-Soluble Vitamins in Relation to Nutritional Status of Patients with Ovarian Cancer

In this study, we aimed to determine serum concentrations of carotenoids and fat-soluble vitamins (FSVs) in ovarian cancer (OC) patients categorized by clinical and nutritional status and to compare obtained results with healthy controls. We used single-step extraction methods throughout the study. Serum concentrations of the bioactive compounds were measured using HPLC. The evaluation of the nutritional status of patients was performed with scored PG-SGA questionnaire. The serum bioactive compound levels were significantly lower in early-stage OC patients (FIGO I/II) when compared to healthy controls for all-trans-retinoic acid, 25-hydroxycholecalciferol, all-trans-retinol, astaxanthin, zeaxanthin, lycopene and α-carotene, respectively. In patients with advanced-stage of OC (FIGO III/IV) the mean serum concentrations of carotenoids and FSVs were significantly lower than in healthy controls, excluding lutein and β + γ-tocopherol levels. Patients with OC and concomitant moderate or severe malnourishment showed significantly lower levels of 25-hydroxycholecalciferol and all-trans-retinol. It seems that our extraction and measurement methods for the bioactive compounds could be used in both, clinical and nutritional studies. The obtained results confirm that the PG-SGA assessment might be considered not only as a malnutrition assessment tool, but also for planning early nutritional intervention in patients with OC.

Impact of nonspecific death on overall survival in early-stage epithelial ovarian cancer patients

To estimate the impacts of nonovarian cancer-specific death (non-OCSD) and ovarian cancer-specific death (OCSD) on early-stage patients, and to determine which statistical method yielded survival results most similar to real-world situations. Data of patients with early-stage epithelial ovarian cancer from 1988 to 2015 registered in the Surveillance, Epidemiology, and End Results database were analyzed. The primary outcome events of epithelial ovarian cancer were OCSD, non-OCSD, or alive. Incidences of non-OCSD and OCSD with different clinicopathological factors, cumulative incidences of non-OCSD and OCSD, and overall survival impact of non-OCSD were analyzed. A total of 1606 non-OCSD (8.9%) and 3022 OCSDs (16.8%) were analyzed. Several independent features were associated with non-OCSD, including age (>60 years), radiotherapy, and marital status. In patients with histology (eg, endometrioid or mucinous), well-differentiated cells, stage I disease, or widowed marital status, as well as age older than 60, non-OCSD rates of all causes of death notably distorted overall survival, resulting in inaccurate and biased interpretations. Overall survival was greatly influenced by non-OCSD in early epithelial ovarian cancer. Future clinical trials should consider non-OCSD as a competing risk event, especially among patients older than 60 years and those with well-differentiated cells, no chemotherapy, and widowed marital status.

OP-49 - Comparison of quality of life between early and advanced stage ovarian cancer patients

Modified Glasgow Prognostic Score (mGPS) is predictive of survival in many advanced cancers, but has not been evaluated in recurrent ovarian cancer (ROC). The aim was to determine validity of mGPS in ROC, investigate its associations with health related quality of life (HRQL) and ECOG performance status (PS).mGPS is based on serum C reactive protein (CRP) and albumin, with scores ranging from 0 (least) to 2 (most). HRQL was measured with EORTC QLQ C-30 and OV-28. χ2 tests for trend were used to examine the relationship between HRQL, PS and mGPS. Cox proportional hazards regression was used to assess associations between mGPS, HRQL, clinicopathological factors, and overall survival (OS).Inflammatory markers were available in 516 of 948 patients in GCIG SBS. 200(39%) had potentially platinum sensitive ROC with ≥ 3 lines of chemotherapy, 316(61%) had platinum resistant ROC. 282(55%), 123(24%), 111(22%) had mGPS of 0, 1, 2, respectively. Median OS (months) was 18.1, 9.6, and 6.6 for mGPS 0, 1, and 2 respectively. mGPS was an independent predictor of OS after adjusting for PS and platinum sensitivity (p < 0.001). mGPS remained a predictor of OS after adjusting for physical function, role function, global health status, abdominal/GI symptoms, and multiple clinicopathologic factors (p = 0.02). Worse PS and higher mGPS were associated with poorer HRQL (p < 0.001). Higher mGPS was associated with worse HRQL, independent of PS.The mGPS is an independent predictor of OS in ROC after adjusting for HRQL and clinicopathological factors. Higher mGPS is associated with worse HRQL independent of PS. mGPS is simple, inexpensive and may be suitable for clinical practice, clinical trial patient selection and stratification.

Abstract 912: Macrophage inhibitory factor (MIF), osteopontin (OPN) and anti-interleukin-8 (IL-8) autoantibodies (AAb) complement CA125 for detection of early-stage ovarian cancer

Abstract Background: Early detection of ovarian cancer promises to reduce mortality. At present, only 20 percent of ovarian cancer is found in early stage (I-II). CA125 is found in sera from approximately 60% of patients with early stage disease. Greater sensitivity could be observed with a panel of blood tests. Methods: A panel of 10 antigen biomarkers (MIF, Leptin, IL-6, IL-8, TNFa, OPN, FGF2, HE4, TGFa and a panel of autoantibodies (AAbs) against 12 antigens (IL-8, MDM2, c-myc, PLAT, EpCAM, HOXA7, ENO1, PDI, HSPA5, HSPA8, ANXA2, Cathepsin D) were analyzed in sera of 77 ovarian cancer patients with early stage (I-II), 50 patients with late stage (III-IV), and 216 healthy women from the Normal Risk Ovarian Cancer Screening Study (NROSS) using Luminex-based immunoassays. Serum levels of serum tumor marker CA-125 were routinely measured in all patients using a Roche assay. The most promising markers (CA125, MIF, OPN, and anti-IL-8 autoantibodies were validated using an independent panel with sera from 69 early stage and 50 late ovarian cancer patients and 200 healthy controls. Result: Serum level of CA125, MIF, OPN and IL-8 AAb were elevated in early stage (I-II) and late stage (III-IV) ovarian cancer patients compared with healthy controls. Analyzing the positive biomarkers in combination with CA125 increased detection of early stage disease from 62% with CA125 alone to 92% a panel of CA125, MIF, OPN and IL-8 AAb at 98% specificity. For patients with late stage disease sensitivity increased from 90% to 98% with the panel. Complementarity of CA125 with MIF, OPN and IL-8 AAb was confirmed with an independent validation set, where sensitivity for early stage disease was improved from 84% to 91% at 98% specificity. Conclusion: MIF, OPN and IL8 AAb could be used in combination with CA125 to distinguish ovarian cancer patients from health controls with high sensitivity. Citation Format: Jing Guo, Wei-lei Yang, Joseph Celestino, Karen Lu, Anna E. Lokshin, Zhen Lu, Robert C. Bast. Macrophage inhibitory factor (MIF), osteopontin (OPN) and anti-interleukin-8 (IL-8) autoantibodies (AAb) complement CA125 for detection of early-stage ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 912.

Osteopontin, Macrophage Migration Inhibitory Factor and Anti-Interleukin-8 Autoantibodies Complement CA125 for Detection of Early Stage Ovarian Cancer.

Early detection of ovarian cancer promises to reduce mortality. While serum CA125 can detect more than 60% of patients with early stage (I–II) disease, greater sensitivity might be observed with a panel of biomarkers. Ten protein antigens and 12 autoantibody biomarkers were measured in sera from 76 patients with early stage (I–II), 44 patients with late stage (III–IV) ovarian cancer and 200 healthy participants in the normal risk ovarian cancer screening study. A four-biomarker panel (CA125, osteopontin (OPN), macrophage inhibitory factor (MIF), and anti-IL-8 autoantibodies) detected 82% of early stage cancers compared to 65% with CA125 alone. In early stage subjects the area under the receiver operating characteristic curve (AUC) for the panel (0.985) was significantly greater (p < 0.001) than the AUC for CA125 alone (0.885). Assaying an independent validation set of sera from 71 early stage ovarian cancer patients, 45 late stage patients and 131 healthy women, AUC in early stage disease was improved from 0.947 with CA125 alone to 0.974 with the four-biomarker panel (p = 0.015). Consequently, OPN, MIF and IL-8 autoantibodies can be used in combination with CA125 to distinguish ovarian cancer patients from healthy controls with high sensitivity. Osteopontin appears to be a robust biomarker that deserves further evaluation in combination with CA125.

Ovarian cancer practice survey from the South Asian Association for Regional Cooperation (SAARC) Nations

Background: Management of ovarian cancer has evolved over time with innovations in surgical management as well as in systemic therapy. In the real world, treatment is often adapted to distinct settings based on the socioeconomic factors, physician and patient preference, availability of resources, need for referral, and controversies in the standard treatment. These deviations from conventional treatment can lead to suboptimal results and a better comprehension of this variability can help us to plan corrective measures for improvement in community practice. Methods: The survey instrument consisted of four sections dealing with baseline details of participants, early-stage ovarian cancer practice patterns, surgical practice patterns, and adjuvant/neoadjuvant chemotherapy (NACT) in advanced-stage ovarian cancer. It was an anonymous survey sent as an email and the responses were electronically captured. No incentive was provided. Descriptive statistics were performed using the SPSS software version 20 and R studio. Results: Seventy-five of 258 participants responded. Majority of participants (n = 67, 89.3%) were in favor of doing a fertility-preserving surgery in early-stage ovarian cancer with 86.7% opting for open surgery (n = 65) and only 13.3% (n = 10) using minimally invasive methods. The proportions of early-stage ovarian cancer patients receiving chemotherapy were >90% in 14.7% (n = 11), 75%–90% in 24% (n = 18), 50%–75% in 18.7% (n = 14), 10%–50% in 32% (n = 24), and Conclusion: Ovarian cancer management in the South Asian Association for Regional Cooperation countries is largely congruent with international guidelines. Differences in the administration of intensive chemotherapy schedules and targeted therapy are observed.

Abstract B20: Simultaneous measurement of 92 serum protein biomarkers for the development of a multiprotein classifier for ovarian cancer detection

Abstract Currently, there are no FDA-approved screening tools for detecting ovarian cancer in the general population. The two most common ovarian cancer biomarkers, CA125 and HE4, when used individually are neither adequately sensitive nor specific enough to be used for screening. We hypothesize that by using a combination of biomarkers for screening, it will be possible to increase the sensitivity and specificity over CA125 alone. Development of a blood-based assay for ovarian cancer detection could significantly improve the survival of patients if it identified cancers earlier. In this study, we used Proseek Multiplex Oncology II plates to simultaneously measure the expression of 92 cancer-related proteins in serum using proximity extension assays. This technology combines the sensitivity of the polymerase chain reaction with the specificity of antibody-based detection methods, allowing multiplex biomarker detection and high-throughput quantification. In a review of the literature, we found that 44 of these 92 proteins had been studied individually and were present at elevated levels in ovarian cancer samples (e.g., serum or tissues). This study is the first to examine the levels of 92 proteins simultaneously using a large cohort of ovarian cancer serum samples. We analyzed one microliter of serum from each of 60 women with late stage (Stages III and IV) high-grade serous ovarian cancer and compared the values obtained to those from 241 age-matched healthy women. The data from these 301 serum samples were normalized across four Proseek Multiplex Oncology II 96-well plates and across the different sources of sera. Principal component analysis and unsupervised hierarchical clustering separated patients into the two major groups of ovarian cancer and healthy, with minimal misclassification. Data from the Proseek plates for CA125 levels exhibited a strong correlation with previously measured clinical values for CA125 (correlation coefficient of 0.90, with a 95% confidence interval of 0.88-0.92). CA125 and HE4 were detected at low levels in healthy samples, while higher levels were found in the ovarian cancer cases. Overall, we identified 45 proteins that showed a significant difference (p &amp;lt; 0.001) between ovarian cancer and healthy samples, many of which could serve as novel serum biomarkers for ovarian cancer. In total, 46 proteins had an estimated area under the ROC curve (AUC) of 0.7 or greater. CA125 alone achieved a sensitivity of 0.92 and a specificity of 0.98. In addition, we generated a multiprotein classifier using 10 proteins (including CA125) that increased the sensitivity to 0.97, while holding the specificity fixed at 0.98. This 5% increase in sensitivity will have a significant effect on the number of women correctly identified when screening a large population. Our data demonstrate that the Proseek technology can replicate the results established by conventional clinical assays for known biomarkers, identify new candidate biomarkers, and improve the sensitivity and specificity of CA125 alone. Additional studies using a larger cohort of early-stage ovarian cancer patients will allow for validation of these biomarkers and lead to the development of a screening tool for detecting early-stage ovarian cancer in the general population. Citation Format: Amy P.N. Skubitz, Kristin L.M. Boylan, Kate Geschwind, Qing Cao, Timothy K. Starr, Melissa A. Geller, Robert C. Bast, Jr., Karen H. Lu, Joseph S. Koopmeiners. Simultaneous measurement of 92 serum protein biomarkers for the development of a multiprotein classifier for ovarian cancer detection. [abstract]. In: Proceedings of the AACR Conference: Addressing Critical Questions in Ovarian Cancer Research and Treatment; Oct 1-4, 2017; Pittsburgh, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(15_Suppl):Abstract nr B20.

Abstract 5404: RNA sequencing-based discovery and validation of a noninvasive microRNA signature for the detection of early-stage ovarian cancer

Abstract Purpose Ovarian cancer (OC) is one of the most lethal gynecological malignancies with a 5-year survival rate of less than 50%. While only 15% of OCs are diagnosed at an early stage (stage 1), more than 75% of these neoplasms at first presentation are already advanced (stage 3 or 4), where a cure is very unlikely and recurrent disease is quite common. Previous attempts at discovering early detection biomarkers for OC have largely failed because of reliance on sub-optimal discovery approaches and the lack of comprehensive patient cohorts. MicroRNAs (miRNAs), which belong to the family of small non-coding RNAs, are frequently dysregulated in cancers including OC. Although several miRNA biomarkers have previously been reported for OC patients, lack of systematic biomarker discovery and validation approach has hampered their clinical translation. To address some of these limitations, we performed a comprehensive and systematic biomarker discovery and validation to identify miRNAs dysregulated in early stage OCs, with the ultimate aim of developing a blood-based early diagnostic assay. Experimental design We performed miRNA expression profiling using a high-throughput small RNA-sequencing in stage 1 ovarian cancer (N=23) and matched normal (N=10) tissues. Differentially expressed miRNAs between cancer and normal tissues were identified using the limma package, which were subsequently validated in a cohort of plasma samples (N=32, healthy individuals and N=32 stage 1 OC patients) using Taqman-based RT-PCR assays. Results Our genome-wide systematic discovery approach led to the identification of eight miRNAs which were significantly upregulated in OC vs. adjacent normal tissues. Of note, even individual miRNAs achieved AUROC values ranging from 0.80 to 0.89; however, the combined panel of these 8 miRNAs achieved an even greater AUROC of 0.90 in detecting stage 1 OC patients (p&amp;lt;0.001). Subsequently, we analyzed this 8-miRNA panel in a set of 64 plasma (N=32, Healthy subjects and N=32, stage 1 OC patients) using RT-PCR assays. We performed binary logistic regression and ROC analysis to evaluate the diagnostic accuracy of these biomarkers. Interestingly, in accordance with the tissue findings, we achieved AUROC values ranging from 0.70 to 0.90 for individual biomarkers, while the combination panel achieved an impressive AUROC of 0.99 (95% CI: 0.98-1.00, p&amp;lt;0.0001) for the identification of early stage ovarian cancer patients. Conclusions In conclusion, our RNA sequencing based comprehensive biomarker discovery identified an 8-miRNA panel that demonstrated a robust diagnostic accuracy in not only tissue specimens, but also in the plasma specimens from early stage OC patients. Further evaluation of these miRNAs in multicenter retrospective and prospective cohorts might lead to the development of a non-invasive diagnostic, as well as a population-screening assay for OC patients. Citation Format: Raju Kandimalla, Wei Wang, Michael Hsieh, Gerald C. Gooden, Monique Spillman, Xin Wang, Bodour Salhia, Ajay Goel. RNA sequencing-based discovery and validation of a noninvasive microRNA signature for the detection of early-stage ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5404.